Opiates

Receptor types, distribution, and effects mediated by each.

(Popular question)

Receptor	Distribution	Effect
Mu	Spinal cord, periaquaductal grey(brainstem), thalamus, cortex	Supraspinal analgesia, resp suppression, euphoria, sedation, decreased GI motility, miosis, physical dependence
Kappa	Spinal cord, periaquaductal grey(brainstem), limbic system, hypothalamus	Spinal analgesia, sedation, dyspnoea,  dysphoria, dependence, inhibition of ADH release
Delta	Olfac bulb, cerebral cortex, Nuc accumbens, amygdala, pontine nucleus	Spinal and supraspinal analgesia, inhibition of GI motility

Tell me about the opiate receptors

• Opioid receptor is a g protein coupled 7 transmembrane receptor.
• Before activation Ca is open and K channel is closed
• When opoid receptor is activated K channel opens in post synaptic nerve and Ca channel closes on presynaptic nerve
• Presynaptic inhibition –> decreased vesicle release–> decrease action of Ach, glutamate, Noradrenaline, 5-HT, substance P
• Facilitate pain inhibition
• Endogenous peptide agents – endorphins, enkephalins, dynorphins
• Most opiates have significant first pass metabolism
• Distribute to highly perfused tissues like brain, kidney, liver lung
• Metabolised to glucuronides in liver and renally excreted.
• Other SE – cough suppression, bradycardia, TOELRANCE, physical and psychological dependence
• Uses – analgesia, dyspnoea, cough, diarrhoea, shivering,

 

Specific agents to know in detail:

Agent	Metabolite	Oral bio avail	T 1/2	Metabolism	Excretion
Morphine	hydromorphone	20-40%	2-3hr	90% hepatic	Renal 90%, biliary 10%	Full agonist at mu
Pethidine	norpethidine	50-60%	2.5-4hr	Hepatic	Renal
Fentanyl	inactive metabolite	33% (92% transderm)			60% urine <10% unchanged	Synthetic, prefered in renal imp,
Codeine	hydrocodone	90%	2.5-3hrs	Hepatic		Mild to mod agonist
Oxycodone	oxymorphone

 

Need some familiarity with:

 

• Papaveretum.
  • Mixture of opioid alkaloids – codeine, morphine and papaverine

 

• Methadone.
  • Synthetic opioid with long half life so used in opioid addiction
  • Potent mu agonist, blocks NMDA and monoamine reuptake
  • Inactive metabolite
  • Bioavail 41-99%
  • Hepatic metabolism
  • 7-65hrs
  • Excretion – urine and faeces

 

• Heroin.
  • Body metabolises it into morphine
  • Bio avail <35%
  • Metabolism – hepatic
  • T 1/2 2-3mins
  • Excretion 90% renally, rest biliary
  • Fast acting and potent

 

• Buprenorphine (Temgesic) is of interest as a partial agonist.
  • Potent and long acting partial mu agonist and kappa antagonist, high doses its antagonist at mu
  • Significant first pass effect
  • Resistent to naloxone reversal
  • Used in detox and heroin maintence

 

• Naloxone.
  • Mu, delta and kappa receptor antagonist
  • Duration of action 1-2hrs when given IV
  • Reverse opiod effect in 1-3mins
  • Can precipitate withdrawal in dependent pts
  • PK – glucuronide conjugation and renal excretion

 

• Naltrexone
  • Mu, delta and kappa receptor antagonist
  • Longer acting, t1/2 10hrs, blocks injected heroin effects for 48hrs
  • Well absorbed orally but has 1st pass effect